Viral Membrane Channels: Role and Function in the Virus Life Cycle

Sze, Ching Wooen; Tan, Yee-Joo

Apoptosis is a genetically programmed mechanism used by the host to eliminate damaged or unwanted cells through the activation of caspase cascade. There are two main signaling pathways that can activate programmed cell death, the extrinsic or receptor-mediated pathway, and the intrinsic or mitochondrial pathway [159, 160] . Perturbation of the ER Ca 2+ storage can also activate an ER-specific apoptotic pathway that ultimately leads to the activation of the common apoptosis effector caspase, caspase-3 [161] . Viroporins from several viruses have been shown to trigger apoptosis in a caspase-dependent manner but the mechanism involved differs between each virus. HCV p7 has been shown to induce apoptosis via both the intrinsic and extrinsic pathways. In addition, mutational analysis indicated that such ability is independent of its ion channel activity [162] . The HIV-1 Vpu protein also induces caspase-dependent apoptosis but it does so by preventing the activation of NF-κB and thereby suppressing the expression of several NF-κB-dependent anti-apoptotic genes, such as Bcl-xL, a member of the Bcl-2 family [163, 164] . Recent work by Madan et al. showed that expression of several viroporins from RNA viruses including 6K of Sindbis virus, M2 of IAV, 2B and 3A of poliovirus, p7 of HCV, and E protein of mouse hepatitis virus A59, are able to activate caspase-3 and lead to the release of cytochrome c from the mitochondria [156] , proving the ability of these viroporins to activate the intrinsic programmed cell death pathway. The secreted form of NSP4 can also activate the intrinsic pathway by translocating to the mitochondria and interacting with the mitochondrial integral proteins, the outer mitochondrial membrane pore (VDAC), and the adenine nucleotide translocase (ANT), leading to the release of cytochrome c and depolarization of mitochondria [157] .